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High Resolution Genomic Scans Reveal Genetic Architecture Controlling Alcohol Preference in Bidirectionally Selected Rat Model

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High Resolution Genomic Scans Reveal Genetic Architecture Controlling Alcohol Preference in Bidirectionally Selected Rat Model Purdue University Purdue e-Pubs Department of Animal Sciences Faculty Department of Animal Sciences Publications 2016 High Resolution Genomic Scans Reveal Genetic Architecture Controlling Alcohol Preference in Bidirectionally Selected Rat Model Chiao-Ling Lo Indiana University School of Medicine Amy C. Lossie Indiana University School of Medicine Tiebing Liang Indiana University School of Medicine Yunlong Liu Indiana University School of Medicine Xiaoling Xuei Indiana University School of Medicine See next page for additional authors Follow this and additional works at: http://docs.lib.purdue.edu/anscpubs Recommended Citation Lo C-L, Lossie AC, Liang T, Liu Y, Xuei X, Lumeng L, et al. (2016) High Resolution Genomic Scans Reveal Genetic Architecture Controlling Alcohol Preference in Bidirectionally Selected Rat Model. PLoS Genet 12(8): e1006178. https://doi.org/10.1371/ journal.pgen.1006178 This document has been made available through Purdue e-Pubs, a service of the Purdue University Libraries. Please contact [email protected] for additional information. Authors Chiao-Ling Lo, Amy C. Lossie, Tiebing Liang, Yunlong Liu, Xiaoling Xuei, Lawrence Lumeng, Feng C. Zhou, and William M. Muir This article is available at Purdue e-Pubs: http://docs.lib.purdue.edu/anscpubs/19 RESEARCH ARTICLE High Resolution Genomic Scans Reveal Genetic Architecture Controlling Alcohol Preference in Bidirectionally Selected Rat Model Chiao-Ling Lo1,2, Amy C. Lossie1,3¤, Tiebing Liang1,4, Yunlong Liu1,5, Xiaoling Xuei1,6, Lawrence Lumeng1,4, Feng C. Zhou1,2,7*, William M. Muir1,3,4* 1 Indiana Alcohol Research Center, Indiana University School of Medicine, Indianapolis, Indiana, United a11111 States of America, 2 Department of Anatomy & Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America, 3 Department of Animal Sciences, Purdue University, West Lafayette, Indiana, United States of America, 4 Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America, 5 Department of Medical Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America, 6 Department of Biochemistry, Indiana University School of Medicine, Indianapolis, Indiana, United States of America, 7 Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States of America OPEN ACCESS ¤ Current address: Genetics, Epigenetics, and Developmental Neuroscience Branch, Division of Neuroscience and Behavior, National Institute on Drug Abuse, NIH, Bethesda, Maryland, United States of Citation: Lo C-L, Lossie AC, Liang T, Liu Y, Xuei X, America Lumeng L, et al. (2016) High Resolution Genomic * [email protected] (FCZ); [email protected] (WMM) Scans Reveal Genetic Architecture Controlling Alcohol Preference in Bidirectionally Selected Rat Model. PLoS Genet 12(8): e1006178. doi:10.1371/ journal.pgen.1006178 Abstract Editor: Greg Gibson, Georgia Institute of Technology, Investigations on the influence of nature vs. nurture on Alcoholism (Alcohol Use Disorder) in UNITED STATES human have yet to provide a clear view on potential genomic etiologies. To address this Received: March 3, 2016 issue, we sequenced a replicated animal model system bidirectionally-selected for alcohol Accepted: June 15, 2016 preference (AP). This model is uniquely suited to map genetic effects with high reproducibil- Published: August 4, 2016 ity, and resolution. The origin of the rat lines (an 8-way cross) resulted in small haplotype blocks (HB) with a corresponding high level of resolution. We sequenced DNAs from 40 Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, samples (10 per line of each replicate) to determine allele frequencies and HB. We achieved transmitted, modified, built upon, or otherwise used ~46X coverage per line and replicate. Excessive differentiation in the genomic architecture by anyone for any lawful purpose. The work is made between lines, across replicates, termed signatures of selection (SS), were classified available under the Creative Commons CC0 public according to gene and region. We identified SS in 930 genes associated with AP. The domain dedication. majority (50%) of the SS were confined to single gene regions, the greatest numbers of Data Availability Statement: The data is available which were in promoters (284) and intronic regions (169) with the least in exon's (4), sug- from the NIH Sequence Read Archive as BAM files (http://trace.ncbi.nlm.nih.gov/Traces/study/) under gesting that differences in AP were primarily due to alterations in regulatory regions. We accession SRP078592. confirmed previously identified genes and found many new genes associated with AP. Of Funding: This work was supported by the National those newly identified genes, several demonstrated neuronal function involved in synaptic Institute of Health P60 AA07611 and AA016698. The memory and reward behavior, e.g. ion channels (Kcnf1, Kcnn3, Scn5a), excitatory recep- funders had no role in study design, data collection tors (Grin2a, Gria3, Grip1), neurotransmitters (Pomc), and synapses (Snap29). This study and analysis, decision to publish, or preparation of the manuscript. not only reveals the polygenic architecture of AP, but also emphasizes the importance of regulatory elements, consistent with other complex traits. Competing Interests: The authors have declared that no competing interests exist. PLOS Genetics | DOI:10.1371/journal.pgen.1006178 August 4, 2016 1/23 Genetic Architecture of Alcohol Preference Author Summary Alcohol Used Disorder (AUD) or Alcoholism extracts a great societal cost in terms of human suffering. Understanding the genetic basis is critical to comprehend, treat and pre- vent this disease, but difficult in humans, as choice is influenced by nature and nurture. To discover its genetic basis, we used an animal model system that controlled for genetic and non-genetic factors through randomization, study replication, long-term divergent selec- tion, and a controlled environment. We conducted whole genome sequencing in breeds that were either compulsive excessive drinkers or completely abstinent. We discovered consistent alterations in several genes and neurological pathways previously unassociated with alcoholism. These results strengthened our understanding of the genetic basis of alco- holism and revealed potential genetic- and neurological-based treatments. Introduction The quest to discover the underlying genetic etiology that contributes to alcoholism (a.k.a. Alcohol Use Disorder, AUD) is an ultimate goal for understanding, preventing and treating alcoholism caused by inherited risk factors. Genomic investigations in humans have yet to determine the genetic causes of this disease due to a number of challenges, including partial or complete confounding of family history with familial drinking behaviors, drinking variability and non-genetic (e.g. social, economical and cultural) factors. Genomic analyses in humans, including genome-wide association studies (GWAS), account for a small proportion of the total genetic variance associated with AUD [1–4]. In addition, reproducibility of results has become a major concern [5]. To address these issues, an animal model with heterogeneous ori- gins [6], combined with replication and randomization (see below), was utilized with the expectation that the model will gain insights into the human condition. The high (HAD) and low (LAD) alcohol drinking rat lines constitute one of the most exten- sively characterized rodent models of human AUD [7]. These bi-directionally selected (>40 generations) and replicated lines [8] exhibit a wide range of alcohol preferences (AP) and other alcohol-related endophenotypes that recapitulate human AUD [7, 9]. The HAD/LAD lines were derived from the NIH heterogeneous stock (NIH-HS) [10] and encompass genetic varia- tion from eight inbred lines. The HAD/LAD demonstrate a major heritable component for AP, providing an attractive model to expose the genetic and neurobiological bases underlying AUDs. The AP trait is characterized by heightened alcohol seeking behavior driven by the reinforc- ing action and other effects of ethanol on the brain. HAD rats show the reinforcing effects through performing an operant response for access to alcohol and attain pharmacologically relevant blood alcohol concentrations (BACs; 50 to 150 mg/dL) in under 24 hours [7]. HAD animals display an alcohol deprivation effect after repeated cycles of access to a single concen- tration of alcohol and an increased response when multiple concentrations of ethanol are used. In contrast, the LAD lines exhibit none of these phenotypes [7]. Although previous studies from our group identified several candidate genes associated with AP on Chrs 5, 10, 12 and 16 in HAD rats [11–13], the QTL resolving power precluded fine mapping of the causative genes. In this study we employed whole genome sequencing to identify regions of excessive differ- entiation associated with AP using the population stratification index (Fst). The Fst identifies genes and gene regions under selection by finding genomic regions with an excessive degree of differentiation [14–17]. While this approach has been tried in a number of studies [18–20], most were inconclusive due to issues related to demography, lack of replication [21] or large PLOS Genetics | DOI:10.1371/journal.pgen.1006178 August 4, 2016 2/23 Genetic Architecture of Alcohol Preference LD blocks. We eliminated
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